
The chemical name of the S-(+)-clopidogrel represented by formula 1 is methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-a]pyridine-5-(4H)-acetate and has been known as an efficacious therapeutic agent for vascular system diseases used for the treatment of peripheral arterial diseases, such as cerebral apoplexy, thrombus, embolus etc., and coronary arterial diseases, such as myocardial infarction, angina pectoris, etc., as it shows a strong platelet aggregation inhibitory activity and an antithrombotic activity.
According to recent researches, it has been shown that the S-(+)-clopidogrel is a very effective agent inhibiting platelet aggregation because it has a strong inhibitory effect against the platelet aggregation even with a small dose compared with aspirin while it minimizes the toxic effects to be given on the gastrointestinal tract.
The S-(+)-clopidogrel is commercially available in the name of “Plavix®” and the tablet of this product contains approximately 98 mg of S-(+)-clopidogrel hydrogen sulphate and approximately 75 mg of S-(+)-clopidogrel base as an active ingredient.
As general processes for the preparation of clopidogrel, the preparation processes disclosed in the U.S. Pat. Nos. 4,529,596, 4,847,265 and 5,204,469 are summarized and represented by the following scheme 1.

According to the processes of the conventional methods disclosed in scheme 1, there is required a continuous optical resolution process of forming a diastereomeric salt (h) by reacting a clopidogrel racemate (g) with an optically active acid, obtaining a pure diastereomeric salt of a dextrorotatory (R) optical isomer containing no levorotatory (L) optical isomers by recrystallization, and subsequently removing the optically active acid to prepare the S-(+)-clopidogrel as an optically pure dextrorotatory isomer.
U.S. Pat. No. 4,847,265 discloses an optical resolution method for the preparation of S-(+)-clopidogrel using a (1R)-(−)-camphorsulfonic acid as an optically active acid. International Patent Publication No. WO 98/51689 discloses a process for the preparation of S-(+)-clopidogrel by performing an optical resolution and subsequent reactions from a compound of formula (e) in scheme 1, wherein R is a nitrile, carboxamide, or carboxylic acid. Moreover, International Patent Publication No. WO 02/059128 discloses a process for the preparation of S-(+)-clopidogrel by carrying out an optical resolution and subsequent reactions from a compound of formula (g) in scheme 1, wherein R is a nitrile, carboxamide, or carboxylic acid.
As described above, the known processes for the preparation of S-(+)-clopidogrel may involve the optical resolution inevitably in a specific step of the continuous preparation processes. However, the optical resolution process of the clopidogrel racemate and an intermediate thereof is very disadvantageous environmentally or economically since it is unavoidable that, as for the levorotatory isomer, at least 50% of the intermediate is wasted. Moreover, in performing the optical resolution process to obtain an optical isomer with high purity, it is essential to repeat the purification process such as recrystallization several times, and thus the resulting yield becomes usually reduced.
International Patent Publication No. WO 98/051689 discloses a method to overcome the above drawbacks, which is summarized and represented by the following scheme 2:

In the conventional process according to scheme 2,2-(2-thienyl)-ethylamine of formula (a) in scheme 2 is reacted with o-chlorobenzaldehyde of formula (j) in scheme 2 and sodium cyanide. The resulting nitrile compound of formula (k) in scheme 2 is converted into an amide compound corresponding to formula (l) in scheme 2 and then converted into a methyl ester compound of formula (m) in scheme 2. An intermediate (m) that is an appropriate form used for the synthesis of clopidogrel may be prepared by reacting with an optically active acid through an optical separation of amide (l) or ester (m). Finally, the optical isomer of formula (m) in scheme 2 is subjected to cyclization with formaldehyde in an acidic medium, thereby preparing clopidogrel.
European Patent No. 0466569 discloses another conventional process, which is summarized and expressed by the following scheme 3:

wherein X is a halogen or a sulfonate group.
In the conventional process according to above scheme 3, methyl 2-amino-(2-chlorophenyl)acetate of formula (n) in scheme 3 is reacted with 2-(2-thienyl)ethanol derivative of formula (o) in scheme 3 to prepare an intermediate of formula (m) in scheme 3 (Process A), or methyl 2-halo-(2-chlorophenyl)acetate of formula (p) in scheme 3 is reacted with 2-(2-thienyl)-ethylamine of formula (a) in scheme 3 to obtain an intermediate of formula (m) in scheme 3 (Process B).
Moreover, International Patent Publication No. WO 99/018110 discloses a process for the preparation of clopidogrel by a reaction between tetrahydrothienopyridine (r) and (R)-2-chloromandelic acid ester with a sulfonate leaving group (q) as shown in the following scheme 4.

However, the conventional process according to scheme 4 using 4,5,6,7-tetrahydro[3,2-c]thienopyridine of formula (r) in scheme 4 has a drawback that it is difficult to be purified by crystallization since it has a low melting point and is readily dissolved in an organic solvent.
As described above, the conventional processes for the preparation of clopidogrel are known to have numerous drawbacks.
Accordingly, an object of the present invention is to provide a process for the preparation of S-(+)-clopidogrel with high optical and chemical purity in a simple manner that a diastereomeric salt is formed from a racemic carboxylic acid intermediate of clopidogrel using a (+)-cinchonine by an optical resolution and then by extraction with a suitable solvent.